Dose Of Pioglitazone Research Articles

Pioglitazone/Metformin

A fixed-dose pioglitazone/metformin tablet is approved in the US and the EU for the treatment of adult patients with type 2 diabetes mellitus who currently have inadequate glycaemic control with metformin monotherapy. In the US, the combination tablet is also approved for the treatment of adult patients with type 2 diabetes who currently have inadequate glycaemic control with pioglitazone monotherapy and for those already receiving a combination of pioglitazone and metformin. Bioequivalence, based on absorption and bioavailability parameters, has been established between the fixed-dose tablets and equivalent doses of pioglitazone and metformin coadministered as separate agents. Combination therapy with pioglitazone plus metformin was significantly more effective at improving both glycaemic and lipid control than metformin plus placebo in patients with type 2 diabetes in a 16-week, well designed trial. Pioglitazone plus metformin demonstrated similar antihyperglycaemic efficacy to that of rosiglitazone plus metformin in a well designed 12-month trial; however, pioglitazone plus metformin was the superior combination in terms of lipid control. In several comparative trials of 1-3.5 years' duration, pioglitazone plus metformin was at least as effective as combination therapy with a sulphonylurea plus metformin in terms of antihyperglycaemic efficacy, but provided superior lipidaemic control with regard to levels of triglyceride and high-density lipoprotein-cholesterol. Pioglitazone plus metformin was generally well tolerated in patients with type 2 diabetes, with adverse events common to metformin monotherapy observed at a similar incidence to that with metformin plus placebo.

Safety and Efficacy of Low-dose Pioglitazone (7.5 mg/day) vs. Standard-dose Pioglitazone (15 mg/day) in Japanese Women with Type 2 Diabetes Mellitus

It is well known that pioglitazone, a potent thiazolidinedione, improves metabolic control. However, weight gain or peripheral edema may be of major clinical concern when using this agent. The purpose of our study was to prospectively evaluate the effects of low-dose pioglitazone (7.5 mg/day) on metabolic control, weight gain and the incidence of edema compared with a standard dose of pioglitazone (15.0 mg/day) in patients with type 2 diabetes mellitus (T2DM). Ninety-five Japanese female patients (mean age 58.4 +/- 10.4 years) with newly diagnosed T2DM were selected for this study. They were randomly divided into the following 2 groups according to therapy regimens, and examined every month for 6 months after diagnosis. Group A consisted of 54 patients treated with low-dose pioglitazone orally; Group B, the control-group, consisted of 41 patients treated with standard-dose pioglitazone orally. The incidence of peripheral edema was significantly much lower in group A (2/54) than in group B (11/41) (p = 0.0014). In addition, % change of body weight during the 6-month treatment in group A was significantly less than that in group B (p < 0.0001). On the other hand, the % change of biochemical parameters including HbA1c did not differ significantly between group A and group B, although glucose and lipid control significantly improved from baseline in both groups. Our results demonstrate the safety and efficacy of low-dose pioglitazone, suggesting that it could be another good choice of treatment for Japanese women with T2DM.

Protective Effect of Pioglitazone Against Endotoxin‐Induced Liver Injury through Prevention of Kupffer Cell Sensitization

Activation of Kupffer cells by lipopolysaccharide (LPS) plays a pivotal role in the onset of pathophysiological events that occur during endotoxemia and intracellular calcium ([Ca]i) is involved in LPS-stimulated cytokine production. TNF-alpha is produced exclusively by the monocyte-macrophage lineage, including Kupffer cells, and pioglitazone has been shown to reduce TNF-alpha production from macrophages. On the other hand, there is increasing evidence that TNF-alpha plays a major role in the initiation and/or progression of multiple organ failure syndrome. Therefore, the purpose of this work was to determine whether pioglitazone could prevent LPS-induced liver injury Rats were given a single oral dose of pioglitazone (500 microg/kg). To assess the sensitization of Kupffer cells, LPS (5 mg/kg) was administered IV and transaminases were evaluated 24 hr later. Kupffer cells were isolated 2 hr after pioglitazone treatment. After addition of LPS, [Ca]i was measured using a microspectrofluorometer with the fluorescent indicator, fura-2, and TNF-alpha was measured by ELISA RESULTS: LPS increased transaminases dramatically and elevation of serum transaminases were diminished markedly by pioglitazone. In isolated Kupffer cells, the LPS-induced increase in [Ca]i and TNF-alpha production were suppressed by treated with pioglitazone Therefore, it is concluded that pioglitazone prevents LPS induced liver injury via a mechanism dependent on suppression of TNF-alpha production from Kupffer cells.

Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that modulate gene expression. Therapeutic agents targeting 2 distinct families of PPARs (alpha and gamma) have been introduced in the United States. The first dual-PPAR agonist, muraglitazar, was reviewed by a US Food and Drug Administration (FDA) advisory committee on September 9, 2005, resulting in a vote of 8:1 recommending approval for its use in controlling blood glucose levels in patients with type 2 diabetes. To evaluate the incidence of death, myocardial infarction (MI), stroke, congestive heart failure (CHF), and transient ischemic attack (TIA) in diabetic patients treated with muraglitazar compared with controls. The source material for this analysis consisted of documents about phase 2 and 3 clinical trials released under public disclosure laws for the FDA advisory committee meeting. All reviewed trials were prospective, randomized, double-blind, multicenter studies enrolling patients with type 2 diabetes and hemoglobin A(1c) levels between 7% and 10%. Patients (N = 3725) were randomized to receive differing doses of muraglitazar, pioglitazone, or placebo as monotherapy or in combination with metformin or glyburide in trials ranging from 24 to 104 weeks. The primary outcome was the incidence of death, nonfatal MI, or nonfatal stroke. A more comprehensive composite outcome included these events plus the incidence of CHF and TIA. In the muraglitazar-treated patients, death, MI, or stroke occurred in 35 of 2374 (1.47%) patients compared with 9 of 1351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls) (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07-4.66; P = .03). For the more comprehensive outcome measure that included TIA and CHF, the incidence was 50 of 2374 (2.11%) for muraglitazar compared with 11 of 1351 (0.81%) for controls (RR, 2.62; 95% CI, 1.36-5.05; P = .004). Relative risks for each of the individual components of the composite end point exceeded 2.1 but were not statistically significant. Incidence of adjudicated CHF was 13 of 2374 (0.55%) muraglitazar-treated patients and 1 of 1351 controls (0.07%) (RR, 7.43; 95% CI, 0.97-56.8; P = .053). Compared with placebo or pioglitazone, muraglitazar was associated with an excess incidence of the composite end point of death, major adverse cardiovascular events (MI, stroke, TIA), and CHF. This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial.

Single‐ and Multiple‐Dose Pharmacokinetics of Pioglitazone in Adolescents With Type 2 Diabetes

This study assessed the single- and multiple-dose pharmacokinetics of 3 doses (15 mg, 30 mg, and 45 mg) of pioglitazone in 36 adolescents with type 2 diabetes. Blood samples were obtained over a 48-hour interval after the first dose (day 1) and over a 72-hour interval after the last dose (day 15) of pioglitazone and were assayed for pioglitazone and active metabolites (M-III and M-IV). Pioglitazone systemic exposure increased dose dependently but was less than dose proportional during multiple dosing. The median peak pioglitazone concentration occurred at 2 hours. The mean half-life was 8 to 9 hours for pioglitazone and 24 to 32 hours for M-III and M-IV, with similar values at each dose level. During multiple dosing, accumulation for pioglitazone was negligible, but it reached 2.5- to 3.0-fold for M-III and M-IV. The sustained total serum concentration of active compounds during multiple dosing provides the basis for once-daily dose administration of pioglitazone in adolescents.

Pioglitazone and reductions in post‐challenge glucose levels in patients with type 2 diabetes

Pioglitazone (PIO) has been shown to decrease insulin resistance in patients with type 2 diabetes, resulting in lowered blood glucose concentrations, lowered plasma insulin levels and lowered haemoglobin A1C (A1C) values. Postprandial glucose control has been recently recognized as an important target for reducing overall glycemic burden in patients with type 2 diabetes. Some authors assert that reductions in postprandial glucose levels may lead to a decrease in cardiovascular risk, one of the major complications associated with diabetes. Data were analysed from a 26-week PIO monotherapy study of 88 patients who underwent a 3-h oral glucose tolerance test (75 g dose) at baseline and last measurement. Change from baseline in area under the curve (AUC) values and hourly glucose concentrations were calculated and analysed at both time points for four medication groups: placebo group and PIO 15, 30 and 45 mg groups. Changes from baseline in fasting plasma glucose (FPG) and A1C also were reported. Glucose AUC was significantly (p < 0.05) different from baseline at 15, 30 and 45 mg doses of PIO. In addition, when compared to placebo, PIO (15, 30 and 45 mg) significantly decreased post-challenge blood glucose AUC (p < 0.05). The mean hourly blood glucose levels at last measurement for PIO 15, 30 and 45 mg all were significantly lower (p < 0.05) than placebo at all four time points. In addition, PIO significantly (p < 0.05) reduced FPG and A1C from baseline to last measurement in a dose-related fashion. PIO significantly reduced post-challenge glucose levels following an oral glucose challenge, leading to improvements in overall glycemic control. Postprandial glucose lowering is one of several metabolic effects of PIO in addition to decreasing insulin resistance and improving some lipids components. Whether these combined metabolic effects can lead to cardiovascular risk reductions may be confirmed by the pending results of cardiovascular outcomes studies with PIO.

The effects of PPAR-? ligand pioglitazone on platelet aggregation and arterial thrombus formation

It has been suggested that peroxisome proliferator-activated receptor (PPAR)-gamma ligands reduce the development of atherosclerosis and myocardial ischemia-reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR-gamma activation would inhibit platelet activation and intra-arterial thrombus formation. Sprague-Dawley rats were fed chow mixed with pioglitazone (1 or 10 mg/kg/day) for 7 to 10 days. A filter soaked in 30% FeCl(3) was applied around the abdominal aorta to study the patterns of arterial thrombogenesis. The aortic blood flow was continuously monitored using an ultrasonic Doppler flow probe. ADP and arachidonic acid-induced platelet aggregation and the expression of constitutive nitric oxide synthase (cNOS) and thrombomodulin in aorta were measured. Pioglitazone feeding delayed the time to occlusive thrombus formation by 40% (P<0.01 vs. control, n=9) without affecting the weight of the thrombus. ADP- as well as arachidonic acid-induced platelet aggregation was also inhibited by pioglitazone feeding (P<0.01 vs. control, n=9). Pioglitazone feeding also upregulated the aortic expression of cNOS and thrombomodulin; both are considered important factors in platelet aggregation and thrombus formation in vivo. The effect of a high dose (10 mg/kg/day) of pioglitazone was not more potent than that of a low dose (1 mg/kg/day). These results indicate that pioglitazone administration decreases platelet aggregation and delays intra-arterial thrombus formation in rats, at least partially, by an increase in the expression of cNOS and thrombomodulin.

Case Study: Five Steps to Freedom: Dose Titration for Type 2 Diabetes Using Basal-Prandial-Correction Insulin Therapy

Mary, age 53, was seen as a new patient. She had a history of type 2 diabetes for 17 years. Her BMI was 31 kg/m2. She had attempted to adhere to lifestyle measures for treatment of diabetes and had previously consulted with diabetes educators. She was fairly active at her job. She was taking 90 units of peakless insulin (glargine) at bedtime in addition to pioglitazone, 45 mg daily; metformin, 1,000 mg twice daily; and glimperide, 8 mg daily. Her hemoglobin A1c (A1C) was 8.5%. She had average prebreakfast glucose readings of 110 mg/dl. At other times of day, there were premeal glucose readings of 170-240 mg/dl and some peak postprandial readings > 300 mg/dl. Under the supervision of her previous health care provider, over a 12-month period of combined glargine and triple oral therapy, the strategies of changing the time of peakless insulin administration to the morning and, later, splitting the peakless insulin dose into equal morning and bedtime components had failed to change her blood glucose pattern. A conceptual diagram of the average daily excursions of blood glucose at the time of her presentation is shown in Figure 1. Figure 1. Pattern of blood glucose suggesting insufficient prandial insulin effect. At the conclusion of the visit, she commented that she wanted to do whatever was necessary to get better results, and she agreed to replace the glimepiride with prandial use of insulin. The glimepiride was discontinued. The pioglitazone dose was reduced to 30 mg daily, with consideration of possible future discontinuation because of cost factors. The metformin was continued. The combined total amount of the starting doses of insulin under a basal-prandial-correction regimen was assigned at 80% of the former peakless insulin dose. The insulin was divided into 36 units of peakless insulin at bedtime and …

Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial

Background: Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. Objective: This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA 1c) value ≤9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. Results: Two hundred fifty-three patients (127 [50.2%] men, 126 [49.8%] women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group ( P < 0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P < 0.001) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) ( P = 0.002) and apo A-I ( P = 0.006). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P < 0.001; HDL-C: 95.3% vs 83.6%, P < 0.05; TG: 40.8% vs 11.0%, P < 0.001). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA 1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. Conclusion: Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM.

Reversal of glucose intolerance by by pioglitazone in high fat diet-fed rats.

The present study was undertaken to determine the effect of pioglitazone (3, 10 and 30 mg/kg p.o.), an insulin sensitizer, on glucose intolerance in high fat diet- (HFD) fed rats (a nongenetic model of insulin resistance). In addition, the effect of pioglitazone (3, 10 and 30 mg/kg p.o.) on diet-induced changes in body weight, plasma glucose, insulin, triglyceride and total cholesterol levels were also determined. The feeding of HFD for 4 weeks produced a significant increase in body weight, total fat pad weight, basal/fasting plasma glucose, insulin, basal triglyceride (TG) and total cholesterol (TC) levels in male rats. Furthermore, the rats fed HFD exhibited fasting hyperglycemia and hyperinsulinemia as well as enhanced glycemic response to exogenously administered glucose (2 g/kg p.o.) during an oral glucose tolerance test (OGTT) at the end of 4 weeks of dietary manipulation, indicating that the rats had developed insulin resistance and glucose intolerance. Treatment with pioglitazone (10 and 30 mg/kg p.o.) once daily for 2 weeks significantly diminished the elevated basal plasma insulin and TG levels in HFD-fed rats. In addition, a statistically significant reduction in TC level was observed only with the high dose of pioglitazone (30 mg/kg p.o.). However, pioglitazone had no significant effect on body weight, total fat pad weight and basal plasma glucose level. Pioglitazone (10 and 30 mg/kg p.o.) significantly reduced fasting hyperglycemia and reversed oral glucose intolerance to normal in HFD-fed rats compared with control normal rats. The above findings suggest that pioglitazone has potent insulin-sensitizing and lipid-lowering properties in a HFD-fed rat model. In conclusion, the present study demonstrates that the adult male rats on a HFD for 4 weeks exhibited the characteristic features of obesity, insulin resistance and glucose intolerance, namely increased body weight, increased total fat pad weight, mild basal/fasting hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and impaired oral glucose tolerance, that closely resemble the human prediabetic obese insulin-resistant and glucose-intolerant state. Further treatment with pioglitazone once daily for 2 weeks significantly ameliorated changes in basal plasma insulin, TG and TC, and reversed oral glucose intolerance to normal in HFD-fed rats, suggesting its potential in the treatment of insulin resistance and glucose intolerance associated with abnormal lipid metabolism.

Substitution of Pioglitazone for Troglitazone in Patients with Type 2 Diabetes

To evaluate the clinical utility of pioglitazone therapy in patients who previously received troglitazone. We undertook an observational study involving patients with type 2 diabetes, who were originally treated with troglitazone and subsequently converted to pioglitazone therapy. Drug efficacy was evaluated by comparing baseline hemoglobin A1c (HbA1c) levels, weight, blood pressure, and lipid profiles (during troglitazone treatment) with corresponding values 6 months after final pioglitazone dose titration. Drug safety was evaluated by review of hepatic enzyme levels and documented reports of side effects. The study cohort consisted of 316 patients in whom pioglitazone therapy was initiated after they had received troglitazone for at least 1 year. Discontinuation of pioglitazone treatment subsequently occurred in 43 patients; in 7 additional patients, no follow-up occurred. We found no significant difference between baseline and follow-up mean HbA1c values. Aspartate aminotransferase levels did not significantly change after 6 months of pioglitazone therapy; however, alanine aminotransferase levels increased by a statistically significant 3.8 U/L (95% confidence interval, 2.6 to 4.9). Pioglitazone treatment was discontinued because of edema in 29 of the 309 evaluable patients (9.4%). Pioglitazone was as effective as troglitazone in maintaining HbA1c levels. The hepatic safety of pioglitazone was also demonstrated.

Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPAR gamma ligand.

In our previous study, a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc(1309) mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPAR gamma agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13-15 times higher than those in the wild-type counterparts at 20 weeks of age. They were reduced dose-dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6-20 weeks of age with suppression to almost the wild-type level at the highest dose. Moreover, up-regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone-treated animals. Dose-dependent reduction of intestinal polyps was observed in Min mice given 100-1600 ppm for 14 weeks, total numbers being decreased to 63-9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPAR gamma agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer.

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus

Objective: The goal of this study was to compare the effects of 2 doses of pioglitazone hydrochloride (a thiazolidinedione insulin sensitizer) with placebo on glycated hemoglobin (HbA1c), insulin sensitivity, and lipid profiles in patients with type 2 diabetes mellitus who had suboptimal glycemic control and mild dyslipidemia.Methods: Patients with type 2 diabetes mellitus (HbA1c ≥6.5% and ≤9.8%) who had not previously received insulin or oral antihyperglycemic medications (OAMs) were randomized to treatment with placebo, pioglitazone 30 mg QD, or pioglitazone 45 mg QD in double-blind fashion for 16 weeks at 41 centers in Canada and Spain.Results: A total of 297 patients were randomized (99 in each group). Overall, 286 (96.3%) were white. Mean (SD) age was 58.4 (10.9) years (range, 24–85 years), mean (SD) body mass index was 31.4 (4.8) kg/m2, mean (SD) duration of type 2 diabetes mellitus was 20.0 (37.4) months, and 30.6% of patients were receiving medication for dyslipidemia. Treatment with pioglitazone 30 or 45 mg QD for 16 weeks reduced mean HbA1c by 0.8% and 0.9% from baseline, respectively (both P < 0.001 vs baseline and placebo). A reduction in HbA1c of 0.2% was observed in the placebo group (P = 0.025). In patients with medium (≥7% to <8%) or high (≥8% to ≤9.8%) baseline HbA1c, both doses of pioglitazone significantly reduced HbA1c (both P < 0.001 vs plcebo). Pioglitazone 30 and 45 mg significantly reduced fasting serum insulin versus placebo (P = 0.008 and P = 0.006, respectively) and increased insulin sensitivity by Homeostasis Model Assessment versus placebo (P = 0.039 and P = 0.001, respectively). Relative to placebo, pioglitazone 30 and 45 mg significantly increased high-density lipoprotein cholesterol (HDL-C [P = 0.028 and P < 0.001, respectively]) and lowered the atherogenic index of plasma (P = 0.018 and P < 0.001, respectively). Pioglitazone 45 mg also significantly reduced serum triglycerides, apolipoprotein B, and total cholesterol:HDL-C ratio versus placebo (P = 0.007, P = 0.015, and P = 0.005, respectively). Pioglitazone 30 and 45 mg were associated with a significant reduction in serum alanine aminotransferase relative to placebo (P = 0.036 and P = 0.005, respectively). Pioglitazone appeared to be safe and was well tolerated.Conclusions: In the present study, pioglitazone 30 and 45 mg produced significant improvements in HbA1c, insulin sensitivity, and lipid profile in OAM-naive patients with type 2 diabetes mellitus with suboptimal glycemic control and mild dyslipidemia.

Pioglitazone, a Specific Ligand of the Peroxisome Proliferator-Activated Receptor Gamma Reduces Gastric Mucosal Injury Induced by Ischaemia/Reperfusion in Rat

Background: The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear receptor that has been implicated in the control of metabolism and numerous cellular processes, including cell cycle control, carcinogenesis, and inflammation. The present study was designed to investigate the effect of the specific PPARγ ligand, pioglitazone, on the mucosal lesions induced by ischaemia and reperfusion (I/R) in rats. Methods: I/R lesions were induced in Wistar rats by applying a small clamp to the coeliac artery for 30 min (ischaemic phase), followed by the removal of the clamp for 3 h (reperfusion phase). Vehicle (saline) or increasing doses of pioglitazone (2.5, 10, and 30 mg/kg i.g.) were given 30 min before exposure to I/R. The animals were killed immediately after the end of the reperfusion phase (time 0) and at 12 and 24 h after I/R. The area of gastric lesions was measured by planimetry, and the gastric blood flow was determined by the H[Formula: See Text] gas clearance method. The gastric mucosal gene expressions of PPARγ, interleukin-1beta (IL-1β), tumour necrosis factor alpha (TNF-α), leptin, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were examined by RT-PCR. In addition, protein expression of COX-2 and leptin was assessed by Western blot. Results: The pretreatment with pioglitazone reduced in a dose-dependent manner the mean lesion area induced by I/R, and this effect was accompanied by a significant increase in the gastric blood flow. The decrease in gastric ulcerations by pioglitazone was also observed 12 and 24 h after the I/R. The PPARγ mRNA was weakly expressed in the intact gastric mucosa, but significantly up-regulated after exposure to I/R at each time interval studied. The expression of IL-1β was not changed significantly after pioglitazone applied i.g. at doses 2.5 and 10 mg/kg, but it was down-regulated at the dose 30 mg/kg. TNFα mRNA was strongly increased after the exposure to I/R, but it was down-regulated after pioglitazone pretreatment. In contrast, both leptin and COX-2 mRNA and protein expression were increased in the gastric mucosa after exposure to I/R. The pretreatment with pioglitazone caused a significant up-regulation of mRNA and protein expression of leptin, reaching its peak at the dose 30 mg/kg i.g. In contrast, COX-2 expression did not change significantly after the 2.5 and 10 mg/kg of pioglitazone, but it significantly decreased after pioglitazone at dose 30 mg/kg given to rats before exposure to I/R. Conclusions: Pioglitazone reduces the acute erosions and deeper gastric lesions induced by I/R. The beneficial effect of this PPARγ ligand on I/R-induced gastric damage may be due to its anti-inflammatory properties, especially to the reduction in TNF-α expression and to up-regulation of leptin mRNA in the gastric mucosa. The inhibition of COX-2 expression by pioglitazone may reflect the anti-inflammatory properties of this compound.